The present invention relates to novel substituted derivatives of 1-benzylimidazole-5-methylidene hydantoins which are useful as pharmaceutical agents, to methods for their preparation, to pharmaceutical compositions which include the compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment as well as the use of these agents as diagnostic tools. The novel compounds of the present invention are antagonists of angiotensin II (AII) useful in controlling hypertension, hyperaldosteronism, congestive heart failure, and glaucoma in mammals.
The enzyme renin acts on a blood plasma .alpha..sub.2 -globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin-converting enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammals, such as rats, dogs, and humans. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of the instant invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of the invention are also useful for the treatment of congestive heart failure, hyperaldosteronism, and glaucoma.
European Patent Application 0253310 discloses angiotensin II receptor blocking imidazoles of the formula ##STR1##
European Patent Application 0291969 discloses tetrazole intermediates to antihypertensive compounds ##STR2##
European Patent Application 401030 discloses substituted imidazo-fused 7-member ring heterocycles of Formula I and Ia ##STR3## which are useful as angiotensin II antagonists.
WO 91/00277 discloses substituted imidazoles useful as angiotensin II blockers ##STR4##
European Patent Applications 403158 and 403159 disclose angiotensin II receptor antagonists of formula ##STR5## in which: R.sup.1 is phenyl, biphenyl, naphthyl, or adamantylmethyl, which are unsubstituted or substituted by 1 to 3 substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.4 -alkyl nitro, CO.sub.2 R.sup.7, tetrazol-5-yl, C.sub.1 -C.sub.4 -alkoxy, hydroxy, SC.sub.1 -C.sub.4 alkyl, SO.sub.2 NHR.sup.7, SO.sub.3 H CONR.sup.7 R.sup.7, CN, SO.sub.2 C.sub.1 -C.sub.4 alkyl, or C.sub.n F.sub.2n1, wherein n is 1 to3;
R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, or (CH.sub.2).sub.0-3 phenyl unsubstituted or substituted by 1 to 3 substituents selected from C.sub.1 -C.sub.4 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.4 alkoxy, or NR.sup.7 R.sup.7 ; PA1 X is a single bond, S, or O: PA1 R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, or C.sub.n F.sub.2n1, wherein n is 1 to 3; PA1 R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.5 alkyl, phenyl-Y-, naphthyl -Y-, or biphenyl -Y-, wherein the aryl groups are unsubstituted or substituted by 1 to 3 substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.4 alkoxy, hydroxy, CO.sub.2 R.sup.7, CN, NO.sub.2, tetrazol-5-yl, SO.sub.3 H, CF.sub.3, CONR.sup.7 R.sup.7, SO.sub.2 NHR.sup.7, C.sub.1 -C.sub.4 -alkyl, or NR.sup.7 R.sup.7, or by methylenedioxy, phenoxy, or phenyl, except that R.sup.4 and R.sup.5 are not both selected from hydrogen or C.sub.1 -C.sub.6 alkyl; PA1 Y is a single bond, O, S, or C.sub.1 -C.sub.6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO.sub.2, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CN, or CO.sub.2 R.sup.7 ; PA1 R.sup.6 is --Z--COOR.sup.6 or --Z--CONR.sup.7 R.sup.7 ; PA1 Z is a single bond, vinyl, CH.sub.2 --)--CH.sub.2 --, methylene optionally substituted by C.sub.1 -C.sub.4 -alkyl, 1 or 2 benzyl groups, thienylmethyl, or furylmethyl, or --C(O)NHCHR.sup.9 --, wherein R.sup.9 is H, C.sub.1 -C.sub.4 -alkyl, phenyl, benzyl, thienylmethyl, or furylmethyl; PA1 each R.sup.7 independently is hydrogen, C.sub.1 -C.sub.4 -alkyl, or (CH.sub.2).sub.m phynyl, wherein m is 0 to 4; and PA1 R.sup.6 is hydrogen, C.sub.1 -C.sub.6 alkyl, or 2-di(C.sub.1 -C.sub.4 -alkyl)amino-2oxoethyl; or PA1 R.sup.5 and R.sup.6 are both hydrogen, R.sup.4 is --Z--COOR.sup.8 and Z is other than a single bond; or a pharmaceutically acceptable salt thereof. PA1 hydrogen, PA1 methyl, PA1 ethyl, PA1 n-propyl, PA1 i-propyl, PA1 n-butyl, PA1 i-butyl, PA1 sec-butyl, PA1 t-butyl, PA1 n-amyl, PA1 i-amyl, PA1 n-hexyl, PA1 aryl, PA1 CH.sub.2 -aryl, PA1 CH.sub.2 -heteroaryl, or PA1 CHJ.sub.2 -cycloalkyl wherein aryl, heteroaryl, and cycloalkyl are as defined below in the detailed description of the invention; PA1 methyl, PA1 ethyl, PA1 propyl, PA1 iopropyl, PA1 n-butyl, PA1 n-pentyl, PA1 2-propenyl, PA1 2-butenyl, PA1 3-butenyl, or PA1 cyclopropyl, PA1 (CH.sub.2).sub.n CO.sub.2 Y or ##STR8## wherein Y is hydrogen or lower alkyl, n is 0 to 1, m is 2 to 5; PA1 hydrogen, PA1 alkyl or branched alkyl of from 1 to 8 carbon PA1 atoms, PA1 --(CH.sub.2).sub.m X(CH.sub.2).sub.n H m=1-6, n=0-6, and X.dbd.O, N, S; PA1 hydrogen, PA1 chlorine, PA1 fluorine, PA1 methyl, PA1 trifluoromethyl, or PA1 methoxy; and PA1 (E) -4-[[2-butyl-5-[[1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-4-imidazolidinylid ene]methyl]-1H-imidazolyl]methyl]benzoic acid and its methyl ester, PA1 (E) -4-[[2-butyl-5-[[2,5-dioxo-1,3bis(4,4,4-trifluorobutyl)-4-imidazolidinylid ene]methyl]-1H-imidazol-1-yl]methyl]benzoic acid and its methyl ester, PA1 (Z) -4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylemthyl)-4-imidazolidinylide ne]methyl]-1H-imidazol-1-yl]methyl]benzoic acid and its methyl ester, imidazol-1-yl]methyl]benzoic acid and its methyl ester, PA1 (E) -4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(3-thienylmethyl)-4-imidazolidinylide ne]methyl]-1H-imidazol-1-yl]methyl benzoic acid and its methyl ester, PA1 (E) -4-[[2-Butyl-5-[[2,5-dioxo-1,3-bis(2-thienylmethyl)-4-imidazolidinylidene] methyl]-1H-imidazol-1-yl]-methyl]benzoic acid and its methyl ester, PA1 (Z) -4-[[2-butyl-5-[[3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imid azolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoic acid and its methyl ester, and PA1 (E) -4-[[2-butyl-5-3-butyl-1-[(2-methyl-4-thiazolyl)methyl]-2,5-dioxo-4-imidaz olidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoic acid and its methyl ester. PA1 n-Bu, PA1 CH.sub.2 Ph; or ##STR10##
U.S. Pat. No. 5,355,040 discloses imidazole-5-acetic acid derivatives of the formula ##STR6## wherein R.sup.1 is lower alkyl, cycloalkyl or, phenyl which may be substituted with 1 to 3 of halogen, nitro, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkyl, lower alkoxyl, benzyloxyl and/or hydroxyl; X.sup.1, X.sup.2 and X.sup.3 are each hydrogen halogen, nitro amino, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl; Y is halogen and R.sup.2 is hydrogen or lower alkyl; provided that X.sup.1 is halogen, lower alkyl, lower alkoxyl, benzyloxyl or hydroxyl when R.sup.1 is unsubstituted or substituted phenyl only with 1 halogen, di(lower alkyl)amino, lower alkyl or lower alkoxyl, and its salts. The compounds are disclosed as having antihypertensive activity.
However, the compounds disclosed in the above references do not disclose or suggest the novel combination of structural variations found in the compounds of the present invention described hereinafter.